Current evidence indicates that multiple genes contribute to the familial predisposition for NIDDM in Pima Indians. To search for such genes, we have undertaken a "candidate gene" approach investigating loci which code for proteins involved in the control of glucose homeostasis. Simultaneously, a random approach was initiated using highly informative chromosomal linkage markers. Our group have chosen chromosome 19 because it carries at least three candidate genes including the insulin receptor gene (INSR), the glycogen synthase gene (GYS), and the gene for a hormone- sensitive lipoprotein lipase (LIPE). The latter gene was selected because of the high prevalence of obesity in Pima Indians which increases the risk for NIDDM. Recently, the myotonic dytrophy gene (DM) on this chromosome was also included as a potential candidate because of the documented insulin resistance in patients affected by this muscular disorder. Highly polymorphic DNA markers within each of these genes were utilized in our study. To cover the rest of chromosome 19, nine additional informative DNA markers (D19S177, D19S76, D19S204, D19S179, D19S47, APOC2, KLK1, HRC, D19S246) were chosen for typing. Each marker is being analyzed for linkage with several phenotypes in Pima Indians including NIDDM, insulin resistance, and obesity.